tbuckley/cabot-search huggingface dataset:
Abstract 6020: The role of <i>TP53</i> mutation status in the response to DNA methyltransferase inhibitor treatment
Authors: Khadra K. Omar, Erin E. Grundy, Olivia Cox, Melissa Hadley, Katherine B. Chiappinelli
Journal: Cancer Research (2023)

Abstract The purpose of this study was to understand the effect of p53 mutation status in ovarian cancer cells on the expression of repetitive elements (REs) following epigenetic treatment. High-grade serous ovarian carcinoma is the most aggressive subtype of ovarian cancer and the 5 year survival rate has remained unchanged for over two decades. Over 90% of high-grade serous ovarian carcinoma (OC) patients have a mutation in the TP53 gene, which encodes the p53 protein. P53 is a transcription factor primarily involved in maintaining genome integrity, but it can also regulate the expression of REs in the genome. REs account for more than half of the genome and these repetitive genomic elements are epigenetically silenced in healthy cells to prevent genome instability. The expression of some REs, such as long interspersed nuclear elements and endogenous retroviruses, are upregulated in human OC patients and cell lines. The mechanism by which p53 regulates expression of REs is not well-understood; the literature documents some instances of p53 activating RE transcription and others of p53 repressing RE transcription, depending on the target elements. We have previously shown that RE expression can be induced by treating OC cells with low doses of DNA methyltransferase inhibitors (DNMTis). Recently, we showed that OC cell lines with mutant p53 have higher baseline expression of REs compared to wild type (WT) cell lines. Treatment of TP53 mutant OC cell lines with DNMTis had a muted effect on RE expression compared to treatment of WT OC cell lines. To explore the relationship between TP53 mutation status and RE expression after DNMTi treatment, OC cell lines with different p53 mutation statuses were treated with 500 nM of the DNMTi 5-azacytidine. We then analyzed the expression of several REs via RT-qPCR and western blot. We hypothesized that TP53 mutant cell lines would have lower DNMTi upregulation of REs than TP53 WT cell lines. While at the RNA level RE expression was variable, at the protein level, we found that DNMTi treatment increased protein levels of several REs in TP53 WT and mutant, but not null, OC cell lines. Future work will examine the feasibility of utilizing these RE proteins as immunotherapy targets in OC. Citation Format: Khadra K. Omar, Erin E. Grundy, Olivia Cox, Melissa Hadley, Katherine B. Chiappinelli. The role of TP53 mutation status in the response to DNA methyltransferase inhibitor treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6020.
Abstract 4194: The FuSion Project of Pan-Cancer Early Screening in Chinese– An integrative study by Fudan University and Singlera
Authors: Chen Suo, Renjia Zhao, Yanfeng Jiang, Yunzhi Zhang, Qiye He, Zhixi Su, Rui Liu, Li Jin, Xingdong Chen
Journal: Cancer Research (2023)

Abstract Background: Cancer is the leading cause of premature deaths. Screening in the population can effectively improve the prognosis by diagnosing cancer early. Previous studies have found that cancer biomarkers, for example, ctDNA methylation and protein biomarkers are clearly associated with the occurrence and development of cancer. To evaluate the performance of reported biomarkers for cancer early screening in real world, we launched an integrative study by Fudan University and SInglera for pan-cancer early detectiON (FuSion) project since 2021. Method: The FuSion Project (NCT05159544) is a prospective and multicenter cohort study of pan-cancer screening in Chinese population. We will construct a stepwise model of risk stratification for screening of multiple cancer types, including lung, esophagus, stomach, liver, pancreatic and colorectal cancers. A total of 50,137 individuals recruited in the Taizhou Longitudinal Study (TLS) between 2012 and 2021 are investigated. Eligible participants are aged 20-75 years and without history of cancer. They have completed a questionnaire and provided blood samples for baseline tests, which measure a total of about 50 indicators in the routine blood work, blood biochemistry, and serum cancer biomarkers, such as carbohydrate antigen 19-9 and carcinoembryonic antigen. Informed consent is obtained from all participants. We build risk stratification models based on risk factors collected in the questionnaire and from baseline test results for each cancer type, respectively. Then, 10,000 high-risk- and 5,000 low-risk individuals of cancers are identified by the cancer-specific risk stratification model. They will be screened by the PanSeerX assay using cancer-related DNA methylation markers, and medically followed-up for at least two years. Sensitivity, specificity, positive- and negative-predictive values of the screening models will be determined based on the true cancer incidences. Finally, we will validate the cancer screening strategies using 10,000 average-risk participants recruited from multiple centers by regular checkups and from other large-scale cohort studies. Citation Format: Chen Suo, Renjia Zhao, Yanfeng Jiang, Yunzhi Zhang, Qiye He, Zhixi Su, Rui Liu, Li Jin, Xingdong Chen. The FuSion Project of Pan-Cancer Early Screening in Chinese– An integrative study by Fudan University and Singlera. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4194.
Abstract 3243: Modulating the brain immune system to fight cancer in 3 dimensions
Authors: Eilam Yeini, Daniella Vaskovich-Koubi, Ron Kleiner, Helena F. Florindo, Ronit Satchi-Fainaro
Journal: Cancer Research (2023)

Abstract Despite the remarkable efficiency of immune checkpoint modulators against primary and metastatic brain neoplasms, there is a low percentage of responders and clinical trials report severe immune-mediated side effects and disease relapse. An accumulated body of evidence show that non-tumor cells within the tumor microenvironment (TME), specifically the brain microenvironment (BME), including tumor vasculature and immune stromal cells, such as astrocytes, microglia and pericytes, dictate the overall therapeutic efficacy. We synthesized a biodegradable, off-the-shelf and cost-effective nano-sized polymeric platform that combines a cancer vaccine with the targeted inhibition of molecular and/or cellular immune suppressive players. These precision nano-sized medicines aim to re-educate and harness patient T-cell response against tumors, leading to an immunological memory able to control tumor relapse without any follow-up treatment. The design of these advanced peptide and RNA immunotherapeutics is guided by the identification of lead immune suppressor factors and tumor-specific antigens and proinflammatory cytokines using novel 3D bio-printed brain tumor-immune models developed in our lab. Using this unique model platform we identified P-selectin as a novel immune checkpoint in the brain regulating cancer cells-microglia and tumor-associated macrophages interactions. Combining a P-selectin inhibitor with our first nano-immunotherapy candidates sensitized brain malignancies mouse models to immune-checkpoint modulators, dramatically increasing disease-free survival rates. Citation Format: Eilam Yeini, Daniella Vaskovich-Koubi, Ron Kleiner, Helena F. Florindo, Ronit Satchi-Fainaro. Modulating the brain immune system to fight cancer in 3 dimensions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3243.
Abstract 4939: Combinatorial approach using covalent menin inhibitor, BMF-219, and/or covalent FLT3 inhibitor, BMF-500, with MEK or BCL2 blockade potentiates therapeutic use in AML
Authors: Brian Law
Journal: Cancer Research (2023)

Abstract Introduction: Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease characterized by a highly diverse genomic landscape. Despite recent advances in therapies, treatment outcome remains variable and largely defined by genomic abnormalities such as gene fusions, copy number alterations and point mutations. Mutations in epigenic modifiers, nucleophosmin (NPM1c), signaling and kinase pathway such as KMT2A-re-arrangements (KMT2A-r), internal tandem duplication (ITD) insertions in FLT3, and NRAS mutations are amongst the highest alterations in AML patients with a propensity towards poor response to treatment and overall disease outcome. Such limitations impact the ability to achieve long-lasting response to treatment and result in therapy-induced resistance eventually leading to relapse. Combinatorial strategies are required to combat resistance and maximize duration of antitumor activity. BCL2 and MEK blockade in combination with menin and/or FLT3 inhibitors potentiates an improved therapeutic strategy to achieve increased antitumor activity and overcome AML resistance. Here we explored the use of our clinical-stage covalent menin inhibitor, BMF-219, and BMF-500, a covalent FLT3 inhibitor, in combination with each other and in combination with BCL2 and MEK inhibitors in MV-4-11 and MOLM-13 cell lines for 4-days, then viability was measured using CellTiter Glo. Results: BMF-219 and BMF-500 as single agents induce effective antitumor activity on MOLM-13 and MV-4-11 cells lines. When dosed in combination, BMF-219 and BMF-500 show beneficial effects affording higher cell killing at lower concentrations. Repeated experiments revealed patterns of increased cell killing is achieved when trametinib, MEK inhibitor, and venetoclax, BCL2 inhibitor, are combined with BMF-219 treatment. Conclusions: Collectively, our studies demonstrate the utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of menin and FLT3 covalent inhibitors. Additionally, we show benefit of combinatorial approaches of menin and FLT3 covalent inhibitors with MEK and BCL2 blockade. These data provide initial pre-clinical evidence for combining pathway specific inhibitors as a promising therapeutic strategy for further investigation in acute leukemia. Citation Format: Brian Law. Combinatorial approach using covalent menin inhibitor, BMF-219, and/or covalent FLT3 inhibitor, BMF-500, with MEK or BCL2 blockade potentiates therapeutic use in AML. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4939.
Abstract 3936: ALK fusion oncogene driven <i>SERPINB4</i> expression enhances tumor survival in NSCLC
Authors: Tzu-Po Chuang, Wei-Yun Lai, Jonatan L. Gabre, Dan E. Lind, Ganesh Umapathy, Abdulmalik A. Bokhari, Bengt Bergman, Linnea Kristenson, Fredrik B. Thorén, Anh Le, Robert Doebele, Jimmy V. Eynden, Ruth H. Palmer, Bengt Hallberg
Journal: Cancer Research (2023)

Abstract Anaplastic lymphoma kinase (ALK) fusion variants in non-small-cell-lung cancer (NSCLC) consist of numerous dimerising fusion partners, with the most common being EML4. Clinical data suggests that the degree of treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs among the variant present in the patient tumor. Therefore, a better understanding the oncogenic signaling networks driven by different ALK-fusion variants is important. Here, we developed highly controlled doxycycline-inducible cell models bearing four different ALK fusion proteins, namely EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, and TFG-ALK, in the context of non-tumorigenic NL20 human bronchial epithelial cells. These were complimented by patient-derived NSCLC cell lines harboring either EML4-ALK-V1 or EML4-ALK-V3 fusions. RNA-seq and phosphoproteomics analysis were employed to identify dysregulated genes and hyper/hypo-phosphorylated proteins associated with ALK fusion expression. Among ALK fusion induced responses, we noted a robust inflammatory signature that included up-regulation of the Serpin B4 serine protease inhibitor in both NL20-inducible cell models and ALK-positive NSCLC patient-derived cell lines. We show that STAT3 is a major transcriptional regulator of SERPINB4 downstream of ALK fusions, along with NF-kB and AP1. The upregulation of SERPINB4 promotes survival of ALK fusion expressing cells and inhibits natural killer (NK) cell-mediated cytotoxicity. In conclusion, our study reveals a novel ALK downstream survival axis that regulates Serpin B4 expression and identifies a molecular target that has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC. Citation Format: Tzu-Po Chuang, Wei-Yun Lai, Jonatan L. Gabre, Dan E. Lind, Ganesh Umapathy, Abdulmalik A. Bokhari, Bengt Bergman, Linnea Kristenson, Fredrik B. Thorén, Anh Le, Robert Doebele, Jimmy V. Eynden, Ruth H. Palmer, Bengt Hallberg. ALK fusion oncogene driven SERPINB4 expression enhances tumor survival in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3936.
Abstract 2202: Role of FadA secreting <i>Fusobacterium nucleatum</i> in initiation and progression of colorectal cancer
Authors: Angela Huang, Anjana Saxena, Mintoo Patel
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is a global disease with poor prognosis. There is an alarming increase in incidence of CRC in younger patients along with well recognized racial disparities. Recent data implicate a role of microbiome in initiation and progression of CRC. Fusobacterium nucleatum (Fn), an oral opportunistic pathogen, has emerged as one of the common pathogens associated with CRC. Fn transformation from commensal to pathogen requires expression of amyloid-like FadA adhesin that plays a key role in its attachment to the colonic mucosal cells resulting in inflammatory, oncogenic, and metastatic changes. CRC initiates as polyps that go on to invade the mucosal layers and metastasize. This study analyzed the significance of Fn as a biomarker in CRC as well as to understand the etiology and metastasis of CRC. Deidentified and delinked formalin fixed paraffin embedded tissue sections from cancerous, precancerous and non-cancerous colorectal biopsies were analyzed for Fn presence and markers in epithelial to mesenchymal transition (EMT) in CRC through immunofluorescence. EMT was studied through biomarkers such as E-cadherin, which is an epithelial cell surface protein, vimentin as an intracellular filament protein normally expressed in mesenchymal cells, and N-cadherin, a cell adhesion molecule that is shown to express aberrantly in some solid tumor cells undergoing EMT. As expected, E-cadherin was abundantly expressed on the surface of epithelial cells while vimentin was found in the stromal cells in the non-cancerous tissue sections. Interestingly, the E-cadherin expression was lower in the cancerous tissue and some cancerous specimens also exhibited the vimentin positive foci within epithelial cells signifying partial EMT. N-cadherin expression was not observed in any of the specimens. The presence of Fn as analyzed through the FadA staining correlated with decline in the E-cadherin expression in some cancer specimens. To further analyze the significance of Fn, a meta-analytic study was conducted from 20 studies that indicated a significant presence of Fn not only in CRC tissues but also in fecal specimens from patients with CRC. A whole genome sequencing analysis corroborated with the abundance of Fn in CRC tissue specimens. These data suggest that analysis for Fn presence offers an attractive opportunity for intervention and targeted treatment for chemo resistant tumors. EMT analysis provides an additional corroboration in early detection of cancer progression which is pivotal in successful treatment of CRC. Citation Format: Angela Huang, Anjana Saxena, Mintoo Patel. Role of FadA secreting Fusobacterium nucleatum in initiation and progression of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2202.
Abstract 5025: Reduced level of protein kinase C iota renders human glioblastoma less invasive and induces apoptosis via modulating Tak1/NF-κB pathway
Authors: Khandker Mohammad Khalid, Wishrawana S. Ratnayake, Avijit Dey, Nuzhat N. Oishee, Mahfuza Marzan, Mildred Acevedo-Duncan
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is characterized by poor therapeutic response and overall survival. It is the most aggressive form of primary brain tumor with a tendency to invade surrounding healthy brain tissues, rendering them largely incurable. In this study, small-interference RNA was used to knock down the expression of protein kinase C PKC-ι. The reduced PKC-ι expression impaired the phosphorylation of LIM kinase 1/2 (LIMK), which is a critical step in cofilin recycling and actin polymerization. Additionally, there was a down-regulation of matrix metalloprotease-9 expression in LN-229 and U87G cells, which coincided with decreased invasion. Therefore, PKC-ι regulates both cytoskeleton rearrangement and cell adhesion, which contributed to cell migration. Silencing of PKC-ι also dampened Transforming growth factor-β (TGF-β)-activated kinase 1 (Tak1) level. TAK1 is an essential component in genotoxic stresses-induced NF-κB-activation and mitogen-activated protein kinase (MAPK)-pathways in GBM. TAK1, when activated, forms a complex with TAB1-3 (Tak1 binding proteins). Our data reveal, reduced Tak1 level after silencing PKC-ι interferes with complex formation and reduces NF-κB-activation. Diminished PKC-ι level also reduces activation of Tak1/JNK axis. This deactivation exerts an anti-oncogenic effect on glioblastoma via suppression of Akt1, c-Myc, and STAT3. This implies PKC-ι may have a crucial role in the activation of Tak1. Reduced migration and invasion in glioblastoma cells upon inhibition of PKC-ι was further confirmed by Scratch assay and Boyden assay. These results indicate that PKC-ι is involved in the control of glioblastoma cell migration and invasion. PKC-ι is a central component of multiple converging and bifurcating pathways and is a potential therapeutic target against GBM survival and infiltration. Citation Format: Khandker Mohammad Khalid, Wishrawana S. Ratnayake, Avijit Dey, Nuzhat N. Oishee, Mahfuza Marzan, Mildred Acevedo-Duncan. Reduced level of protein kinase C iota renders human glioblastoma less invasive and induces apoptosis via modulating Tak1/NF-κB pathway. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5025.
Abstract 2673: Several LSD1 inhibitors have a potential to disturb fatty acid metabolism necessary &amp;It glycolysis-inhibited pancreatic cancers to survive
Authors: Zhiheng Zhang, Haruna Aoki, Keitaro Umezawa, Taichi Oshima, Takuya Hirao, Yuri Miura, Kousei Ito, Shigeki Aoki
Journal: Cancer Research (2023)

Abstract Despite increased aerobic glycolysis is generally seen in human cancers, pancreatic ductal adenocarcinoma (PDAC) cells keep alive in glycolysis-suppressed conditions (1). Here, we sought there are potential therapeutic targets in glycolysis-suppressed PDAC cells. By screening anti-cancer metabolism compounds, we identified SP2509, a selective lysine specific demethylase 1 (LSD1) inhibitor (2). We also tested the effect of another three LSD1 inhibitors (Iadademstat, OG-L002 and T-3775440) on PDAC cells viability. The results showed that OG-L002, but not Iadademstat or T-3775440, lowered glycolysis-suppressed PDAC cells viability, like SP2509. Importantly, only knockdown of LSD1 or LSD2 failed to lower the viability of glycolysis suppressed PDAC cells. In our previous study, we proved that glucose-starvation make PDAC cells yield survival to mitochondrial oxidative phosphorylation (1). In this study, we cleared fatty acids metabolism played a crucial role for glycolysis suppressed PDAC cells survival. Then, we confirmed that SP2509 and OG-L002 can lead lipid droplets accumulation in glycolysis-suppressed conditions. In conclusion, our results showed that SP2509 and OG-L002 may involve regulatory effects on lipid droplets homeostasis, which control storage and release of fatty acids, not only by targeting LSD1 or LSD2. Moreover, SP2509 and OG-L002 significantly lowered viability of glycolysis-suppressed PDAC cells, supposing a novel therapeutic potential of approaches to override resistance of glucose-starvation in PDAC cells. 1.Shiratori R, Furuichi K, Yamaguchi M, Miyazaki N, Aoki H, Chibana H, et al. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner. Sci Rep. 2019;9(1):18699. 2.Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SGT, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2017;31(7):1658. Citation Format: Zhiheng Zhang, Haruna Aoki, Keitaro Umezawa, Taichi Oshima, Takuya Hirao, Yuri Miura, Kousei Ito, Shigeki Aoki. Several LSD1 inhibitors have a potential to disturb fatty acid metabolism necessary &amp;It glycolysis-inhibited pancreatic cancers to survive [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2673.